Transcription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing

• Published in: Nature communications 2023-04, Vol.14 (1), p.2318-2318, Article 2318
• Main Authors: Shu, Xueqin, Shi, Yingying, Huang, Yi, Yu, Dan, Sun, Baolin
• Format: Article
• Language: English
• Subjects: 14/28; 38; 38/1; 38/15; 38/22; 38/39; 38/70; 38/71; 38/77; 38/88; 38/90; 631/326/22/1434; 631/92/458/2386; 692/699/255/1318; 82/58; 82/80; 82/83; Anti-Bacterial Agents - therapeutic use; Antibiotic resistance; Antibiotics; Bacteria; Cell walls; Cysteine; Cysteine - metabolism; Drug resistance; Gene regulation; Gene silencing; Genes; Humanities and Social Sciences; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Hydrogen Peroxide - pharmacology; Microbial Sensitivity Tests; multidisciplinary; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Oxidation; Proteomics; Science; Science (multidisciplinary); Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - genetics; Staphylococcus aureus - metabolism; Transcription; Vancomycin; Vancomycin - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37949-0

Treatment of Staphylococcus aureus infections is a constant challenge due to emerging resistance to vancomycin, a last-resort drug. S-nitrosylation, the covalent attachment of a nitric oxide (NO) group to a cysteine thiol, mediates redox-based signaling for eukaryotic cellular functions. However, its role in bacteria is largely unknown. Here, proteomic analysis revealed that S-nitrosylation is a prominent growth feature of vancomycin-intermediate S. aureus . Deletion of NO synthase (NOS) or removal of S-nitrosylation from the redox-sensitive regulator MgrA or WalR resulted in thinner cell walls and increased vancomycin susceptibility, which was due to attenuated promoter binding and released repression of genes involved in cell wall metabolism. These genes failed to respond to H 2 O 2 -induced oxidation, suggesting distinct transcriptional responses to alternative modifications of the cysteine residue. Furthermore, treatment with a NOS inhibitor significantly decreased vancomycin resistance in S. aureus . This study reveals that transcriptional regulation via S-nitrosylation underlies a mechanism for NO-mediated bacterial antibiotic resistance. Antibiotic resistance in Staphylococcus aureus is increasingly emerging. Here, Shu et al demonstrate that transcriptional regulation by S-nitrosylation underlies vancomycin resistance.